This project studies the mechanisms underlying the pathophysiology of a new murine metabolic disease, nm1633, characterized by growth retardation nd progressive polycystic kidney disease (PKD). Although nm1633 is inherited as an autosomal recessive, renal pathology is remarkably similar to human autosomal dominant PKD. Initial genetic mapping studies crossing nm1633- C57BL/6J mice with other inbred strains, MEV/1Ty and CAST/Ei, showed that genetic background has a strong effect on disease progression. in the F2 generation, affected animals have a wide variation in disease phenotype with some developing particularly severe renal disease as young adults while others develop few or no gross cysts even by 10 months of age. These results indicate that nm1633 is a particularly useful animal model for the identification genetic modifiers. A major goal of this proposal is positional cloning of the nm1633 mutation on Chromosome 8 and identifying the homologous region in the human genome. In addition, quantitative trait analysis will be used to map modifier genes that effect cystogenesis. Candidate gene cDNAs that are over-expressed or under-expressed in nm1633 kidneys will be identified, mapped, and sequenced. Candidate genes that do not map near nm1633 may represent modifier genes or, alternatively, may represent other genes required for normal renal development and physiology. Our long term goal is to identify possible modes of therapy for human inherited renal diseases, such as PKD, using mouse genetics as a powerful tool to study interacting systems in kidney development and metabolism.